Antibodies against GPR64 and uses thereof

Active Publication Date: 2007-10-02
ABBOTT BIOTHERAPEUTICS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0031]In an alternative embodiment, the invention provides a method of producing high serum titers of specific antibodies to cell surface receptor proteins comprising: providing a cell surface receptor with a mutation that uncouples the receptor from it signaling system; transfecting and expressing the mutant receptor in a cell line; and passively immunizing a mammal with the cell line; w

Problems solved by technology

(1993) JAMA 270: 2813-2818) however, even bilateral oophorectomy may not be completely effective in preventing ovarian cancer.
Although many ovarian cancer patients are effectively treated, the current therapies can a

Method used

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  • Antibodies against GPR64 and uses thereof
  • Antibodies against GPR64 and uses thereof
  • Antibodies against GPR64 and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

GPR64 Gene Expression Profiling in Ovarian Cancer and Normal Tissues

[0152]This example describes the use of GeneChip expression profiling to identify GPR64 as a valid ovarian cancer target.

SUMMARY

[0153]Gene expression of 66 ovarian cancer samples was compared to 347 normal adult tissues representing 58 different organs. The goal was to look for genes that are up-regulated in ovarian cancer and are localized to the cell surface for antibody accessibility, but have little to no expression in vital organs to minimize undesirable side effects of a therapeutic antibody. Genes with the desired expression profile were examined by extensive bioinformatic analysis to determine their structural and functional classification, and determine their potential for cell surface localization. The GPR64 gene (National Center for Biotechnology Information reference sequence no. NM—005756.1;Ref. Osterhoffet al., 1997, DNA Cell Biol. 16:379-389) displayed all the desired characteristics.

[0154]RNA Extract...

example 2

Anti-GPR64 Inhibits Tumor Cell Growth In Vivo

[0159]The following example illustrates that GPR64 antibodies are effective at reducing tumor volume in vivo.

[0160]Animal studies were conducted using SCID mice immunized with the Human tumor cell line NCI-H460. The NCI-H460 cell line expresses the antigen recognized by antibody GPR64-18. The VH and VL nucleotide and amino acid sequences of antibody GPR64-18 are provided in FIG. 2 (SEQ ID NOs:7,8,17,18).

[0161]The antibodies were made via standard methods using a fusion protein between the large N-terminus of GPR64 and human Fc as the immunogen.

[0162]To initiate tumor growth in vivo SCID mice were injected with the NCI-H460 tumor cell line and tumors were allowed to grow. When tumors reach a size of between 50-100 mm3, animals were distributed into groups and subjected to treatment with either:[0163]a.) an isotype control antibody;[0164]b.) one of the five GPR64 antibodies, whose VH and VL sequences depicted in FIG. 2 (SEQ ID NOs:2-22), or...

example 3

GPR64 Knockdown by RNAi Inhibits Cell Proliferation of GPR64 Expressing Cancer Cells

[0171]The following example illustrates that GPR64 expression is essential for tumor cell growth in vitro and validates GPR64 as an ovarian cancer target.

[0172]Proteins can be down-regulated using short interfering double stranded RNAs (siRNA) specific to the cognate mRNA of the protein of interest. This approach was used to show that inhibition of GPR64 down-regulates cell growth and causes cell death. Thus, these experiments are consistent with the results of the experiments described in Example 2 and thereby confirm the basic conclusion that down-regulation of GPR64 expression will provide an effective treatment for cancers involving GPR64 protein expression.

RNAi Assay Method

[0173]Plasmids encoding an siRNA specific for GPR64, or a control siRNA, were introduced into two GPR64+human tumor cell lines that require GPR64 for growth: H460, Me180. In addition, the same siRNAs were introduced into GPR64...

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Abstract

GPR64 antibody compositions are provided. These antibodies may be used for diagnosis or treatment of cancer, especially ovarian cancer, Ewing's sarcoma, uterine cancer, and other GPR64 expressing tumor types.

Description

RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Application No. 60 / 435,618 filed Dec. 20, 2002, which is hereby incorporated by reference in its entirety. This application is related to U.S. Ser. No. 60 / 350,666 filed Nov. 13, 2001, and U.S. Ser. No. 10 / 173,999, filed Jun. 17, 2002, each of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The invention relates to the identification and generation of antibodies that specifically bind to GPR64 proteins; and to the use of such antibodies and compositions comprising them in the diagnosis, prognosis and therapy of cancer.BACKGROUND OF THE INVENTION[0003]Ovarian cancer is the sixth most common cancer in women, accounting for 6% of all female cancers. It ranks fifth as the cause of cancer death in women. The American Cancer Society predicts that there will be about 23,100 new cases of ovarian cancer in this country in the year 2000 and about 14,000 women will die of the d...

Claims

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Application Information

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IPC IPC(8): C12N5/20A61K39/395A61K45/06C07K14/705C07K16/28C07K16/30
CPCA61K39/39558A61K45/06C07K14/705C07K16/28C07K16/30C07K16/3069A61K2039/505C07K2319/30C07K2317/56C07K2317/77A61K2300/00A61P15/00A61P35/00A61P35/02A61P43/00
Inventor LAW, DEBBIEWANG, QIDUBRIDGE, ROBERTBHASKAR, VINAY
Owner ABBOTT BIOTHERAPEUTICS CORP
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